Programmed Cell Death-1 (PD-1) anchoring to the GPI-linked co-receptor CD48 reveals a novel mechanism to modulate PD-1-dependent inhibition of human T cells

Mol Immunol. 2023 Apr:156:31-38. doi: 10.1016/j.molimm.2023.02.007. Epub 2023 Mar 6.

Abstract

Activation of PD-1 by anchoring it to Antigen Receptor (AR) components or associated co-receptors represents an attractive approach to treat autoimmune conditions. In this study, we provide evidence that CD48, a common lipid raft and Src kinase-associated coreceptor, induces significant Src kinase-dependent activation of PD-1 upon crosslinking, while CD71, a receptor excluded from these compartments, does not. Functionally, using bead-conjugated antibodies we demonstrate that CD48-dependent activation of PD-1 inhibits proliferation of AR-induced primary human T cells, and similarly, PD-1 activation using PD-1/CD48 bispecific antibodies inhibits IL-2, enhances IL-10 secretion, and reduces NFAT activation in primary human and Jurkat T cells, respectively. As a whole, CD48-dependent activation of PD-1 represents a novel mechanism to fine tune T cell activation, and by functionally anchoring PD-1 with receptors other than AR, this study provides a conceptual framework for rational development of novel therapies that activate inhibitory checkpoint receptors for treatment of immune-mediated diseases.

Keywords: Immuno-receptor agonism; Novel immuno-modulation; Programmed Cell Death-1 (PD-1); T cell inhibition.

MeSH terms

  • Apoptosis
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation*
  • Programmed Cell Death 1 Receptor*
  • src-Family Kinases

Substances

  • Programmed Cell Death 1 Receptor
  • src-Family Kinases